Use of N-acetylated amino acid complexes in oral care compositions

ABSTRACT

The subject invention encompasses methods and compositions comprising N-acetylated amino acid complexes for reducing or preventing dental plaque, calculus, or gingival or periodontol diseases of the oral cavity in humans or lower animals.

This is a division of application Ser. No. 07/905,963, filed on Jun. 29,1992, now U.S. Pat. No. 5,286,480.

TECHNICAL FIELD

The subject invention relates to oral compositions used for theprevention of accumulation of plaque and calculus on teeth.

BACKGROUND OF THE INVENTION

Dental plaque is a non-calcified accumulation primarily comprising oralmicroorganisms and their products. Within a few hours after teethcleaning, a film of salivary mucus, consisting primarily of proteins,forms a pellicle on the teeth. Various oral bacteria colonize the mucusand multiply, forming a layer of plaque. Carbohydrate food debris adhereto the mucus and are digested by some types of plaque causing bacteria.The digestion produces by-products which add to the plaque and producesacid which erodes tooth enamel. The plaque adheres tenaciously to theteeth and is not easily dislodged. Depending on bacterial activity andenvironmental factors, plaque may lead to caries or inflammatory changesin tissue adjacent to plaque coated teeth.

If not prevented or removed, plaque may become embedded with mineralsalts, containing calcium and phosphate, to form a hard crusty deposit,calculus or tartar, on the teeth. Calculus may be white or yellowish incolor or may be stained or discolored by extraneous agents. Calculustends to be more unsightly than plaque and much more difficult to removefrom the teeth. The toxins in plaque and calculus can irritate thegingival tissues surrounding the coated teeth, causing inflammation anddestruction of the gums which can lead to other complications.

It is an object of the subject invention to provide compositions forimpeding plaque accumulation.

SUMMARY OF THE INVENTION

The subject invention encompasses compositions for reducing orpreventing dental plaque, or gingival or periodontal diseases, of theoral cavity in humans or lower animals comprising a safe and effectiveamount of a complex of metal ion with N-acetylated amino acid whereinthe metal ion is selected from the group consisting of In³⁺, Ga³⁺, andAl³⁺ ; and a pharmaceutically-acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the subject invention comprise a complex of a metalion with one or more N-acetylated amino acids in apharmaceutically-acceptable topical oral carrier.

"Pharmaceutically-acceptable topical oral carrier", as used herein,denotes a carrier for the active compound or compounds of the subjectinvention (hereinafter "Active" or "Actives") comprising solid or liquidfiller diluents suitable for use in contact with the oral tissues ofhumans and lower animals without undue toxicity, incompatibility,instability, irritation, allergic response, and the like, commensuratewith a reasonable benefit/risk ratio. Such topical oral carrier, whencombined with an Active, results in a composition which is administeredtopically to the oral cavity. Preferably such compositions are held inthe oral cavity for a period of time, and then largely expectoratedrather than being swallowed. Such compositions include mouthwashes,mouth rinses, mouth sprays, dental treatment solutions, toothpastes,dental gels, tooth powders, prophylaxis pastes, lozenges, chewing gumsand the like and are more fully described hereinafter. Dentifrices andmouthwashes are the preferred compositions.

By the term "metal ion", as used herein, is meant Al³⁺, Ga³⁺, or In³⁺.

As used herein, "alkyl" means a carbon-containing chain which may bestraight, branched, or cyclic; substituted (mono- or poly-) orunsubstituted; saturated, monounsaturated (i.e., one double or triplebond in the chain), or polyunsaturated (i.e., two or more double bondsin the chain; two or more triple bonds in the chain; one or more doubleand one or more triple bonds in the chain).

As used herein, "amino acid" includes any naturally or non-naturallyoccurring, L- or D-configuration, preferably L-, organic acid having thestructure ##STR1## wherein--R' is selected from the group consisting ofhydrogen and alkyl having from about 1 to about 12 carbon atoms.

As used herein, amino acids include "naturally occurring amino acids"which are glycine, alanine, valine, isoleucine, leucine, phenylalanine,proline, methionine, serine, threonine, tyrosine, tryptophan,asparagine, glutamine, cysteine, aspartic acid, glutamic acid, lysine,arginine, and histidine.

As used herein, "N-acetylated amino acid" includes any amino acidsubstituted with an acetyl group as in the following structure: ##STR2##

The Actives

The subject invention provides a plaque inhibiting compositioncomprising certain Actives which are complexes of metal ions withN-acetylated amino acids. The ratio of metal ion to N-acetylated aminoacid is preferably from about 1:4 to about 1:1, more preferably fromabout 1:3 to about 1:1.

While not limited to such structures, the metal ion/N-acetylated aminoacid complex is believed generally to conform to the followingstructure:

    R.sub.n M.sub.3 (OH).sub.9-n

In the above structure, each M is independently a metal selected fromthe group consisting of indium, gallium, and aluminum. Preferred is allM being the same; more preferred is all M being aluminum.

In the above structure, each R is independently selected fromN-acetylated amino acids. Preferably R is an N-acetylated naturallyoccurring amino acid; more preferably R is an N-acetylated naturallyoccurring L-amino acid; more preferably still R is N-acetyl-L-glutamineor N-acetyl-L-cysteine. Preferred is all R being the same.

In the above structure, n is an integer in the range of 3 to 9. Eachmetal ion in the Active must be bound to at least one N-acetylated aminoacid, thus n must be at least 3. Preferably n is about 5.

An example of such an Active, N-acetyl-L-glutamine aluminum salts, isdisclosed in U.S. Pat. No. 3,787,466 issued to Kagawa et al. on Jan. 22,1974 and is incorporated by reference herein.

Mixtures of Actives may be used as the active agent in the compositionsof the subject invention. For example, N-acetyl-L-glutamine aluminumsalts may be combined with N-acetyl-L-glycine aluminum salts;N-acetyl-L-asparagine indium salts may be combined withN-acetyl-L-cysteine indium salts; N-acetyl-L-leucine gallium salts maybe combined with N-acetyl-L-arginine aluminum salts. Such examples ofmixtures are given here by way of example, and not for purposes oflimitation.

The Actives of the subject invention are soluble in conventional oralcare compositions, such as mouthwashes, mouth rinses, and toothpastes.However, oral care compositions of the subject invention should besubstantially free from materials known to complex strongly withaluminum, gallium, or indium or to form insoluble precipitates withthose metal ions. Materials to avoid include fluoride ions, phosphateions, metal ion chelators such as ethylenediaminetetraacetic acid (EDTA)or nitrilotriacetic acid (NTA), and others. Inclusion of substantialquantities of these substances in a composition tends to negate theefficacy of the Actives and to reduce anti-plaque activity.

It has been unexpectedly found that treatment of teeth with Actives ofthe subject invention leads to a dramatic reduction in bacteria bindingto the tooth surface. While the anti-plaque activity of the Actives isnot limited by the following, it is believed that such activity is atleast partially achieved in the manner described hereinbelow. Thehydroxyapatite surfaces of teeth possess phosphate and calciumreceptors. The Actives possessing metal ions of aluminum, gallium orindium bind to the phosphate receptors while displacing some or all ofthe N-acetylated amino acid components of the Actives. The N-acetylatedamino acid component of the Active, being more weakly complexed to themetal ion, is displaced by the phosphate group attached to thehydroxyapatite surface. The result appears to be a metal phosphatecoating on the hydroxyapatite surface. Hydroxy groups and water appearto be bound to the metal ions forming a hydrophilic hydrous gel layer.The gel layer inhibits bacteria from obtaining access and binding tosaliva proteins in the pellicle on the tooth surface. Because bacteriaare impeded from adhering to the teeth, fewer are present on the toothsurface to multiply. The result is a reduction in bacterialaccumulation, therefore in plaque and gingivitis when used in the oralcavity.

Additionally, the Actives coagulate colloidal particles like bacteria.The hydrolized metal cations may attach to saliva proteins and bacteria.The decrease in electrostatic inter-bacterial repulsions may lead to theadditional benefit of aiding in the aggregation and clearance ofbacteria from the oral cavity.

Although other materials are known to prevent bacterial adhesion, mostof these materials are polymers which can impart an unpleasant increasein mouth rinse viscosity when used at effective concentrations. TheActives of the subject invention, not being polymers, do not have thisundesirable property. Additionally, the Actives are not easily displacedfrom the tooth surface by saliva. This allows treatment to persistlonger than treatments using most other active compounds targeted atpreventing adherence. Also, use of Actives of the subject inventionavoids the unpleasant taste and staining characteristics of commonlyused antimicrobials.

Compositions

Compositions of the subject invention preferably comprise aqueoussolutions of Active. Such compositions typically comprise from about0.05% to about 10% by weight, preferably from about 0.1% to about 5% byweight, and most preferably from about 0.5% to about 3% by weight ofActive. For a mouth rinse formulation, the most preferred concentrationof Active ranges from about 1% to about 2% by weight.

By "safe and effective amount" as used herein is meant an amount ofcompound or composition sufficient to induce a significant positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The safe and effective amount of thecompound or composition will vary with the particular condition beingtreated, the age and physical condition of the patient being treated,the severity of the condition, the duration of the treatment, the natureof concurrent therapy, the specific compound or composition employed,the particular pharmaceutically-acceptable carrier utilized, and likefactors.

By the term "comprising", as used herein, is meant that variousadditional components can be conjointly employed in the compositions ofthis invention.

Components of the topical, oral carrier are suitable for administrationto the oral cavity of a human or lower animal and are compatible withone another and the other components, especially the Active, used in anoral composition of the subject invention. The term "compatible" as usedherein, means that the components are capable of being co-mingled withone another, in a manner such that there is no interaction which wouldsubstantially reduce the efficacy of the oral composition under ordinaryuse conditions. Preferred topical, oral carriers thus provide thedesired characteristics for mouthwashes, mouth rinses, mouth sprays,dental treatment solutions, toothpastes, dental gels, toothpowders,prophylaxis pastes, lozenges, chewing gums, and the like. The topical,oral carriers of the subject invention comprise components typicallyused in such compositions which are well known to a skilledpractitioner. Such components include, but are not limited to,anticaries agents, antiplaque agents, anticalculus agents, dentalabrasives, surfactants, flavoring agents, sweetening agents, binders,humectants, thickening agents, buffering agents, preservatives, coloringagents and pigments, ethanol and water.

Water is an optional component of the topical, oral carriers of thecompositions of the subject invention. Water employed in the preparationof the commercially suitable compositions should preferably be of lowion content and free of organic impurities. Water preferably comprisesfrom about 2% to about 99%, more preferably from about 20% to about 95%of the compositions of the subject invention. When in the form oftoothpaste, the compositions preferably comprise from about 2% to about45%, more preferably from about 30% to about 40%, water, whilemouthwashes comprise preferably from about 45% to about 95%, morepreferably from about 75% to about 90%, water.

Dental abrasives useful in the topical, oral carriers of thecompositions of the subject invention include many different materials.The material selected must be one which is compatible with thecomposition of interest and does not excessively abrade dentin. Theseinclude, for example, silicas, including gels and precipitates, calciumcarbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate,tricalcium phosphate, calcium polymetaphosphate, insoluble sodiumpolymetaphosphate, hydrated alumina, and resinous abrasive materialssuch as particulate condensation products of urea and formaldehyde, andother materials such as those disclosed by Cooley et al. in U.S. Pat.No. 3,070,510, issued Dec. 25, 1962, incorporated herein by reference.Mixtures of abrasives may also be used.

Silica dental abrasives, of various types, can provide the uniquebenefits of exceptional dental cleaning and polishing performancewithout unduly abrading tooth enamel or dentin. For this reason they arepreferred for use herein.

The silica abrasive polishing materials useful herein, as well as theother abrasives, generally have an average particle size ranging betweenabout 0.1 and 30 microns, preferably between about 5 and 15 microns. Thesilica abrasive can be precipitated silica or silica gels such as thesilica xerogels described in U.S. Pat. No. 3,538,230, issued Mar. 2,1970 to Pader et al., and in U.S. Pat. No. 3,862,307, issued Jun. 21,1975 to DiGiulio, both incorporated herein by reference. Preferred arethe silica xerogels marketed under the tradename Syloid® by the W. R.Grace & Company, Davidson Chemical Division. Preferred precipitatedsilica materials include those marketed by the J. M. Huber Corporationunder the tradename, Zeodent®, particularly the silica carrying thedesignation Zeodent 119®. These silica abrasives are described in U.S.Pat. No. 4,340,583, Wason, issued Jul. 20, 1982, incorporated herein byreference.

Mixtures of abrasives may be used. The amount of abrasive in thecompositions described herein ranges from about 6% to about 70%,preferably from about 15% to about 50%, when the dentifrice is atoothpaste. Higher levels, as high as 90%, may be used if thecomposition is a tooth powder.

Flavoring agents can also be added to the oral compositions of thesubject invention to make them more palatable. Suitable flavoring agentsinclude menthol, oil of wintergreen, oil of peppermint, oil ofspearmint, oil of sassafras, and oil of clove. Flavoring agents aregenerally included in the subject compositions in amounts of from about0% to about 3%, preferably from about 0.04% to about 2% by weight.

Coloring agents may be added to compositions of the subject invention toimprove appearance. If present, coloring agents typically are includedat levels of from about 0.001% to about 0.5% by weight.

Sweetening agents are also preferred in the compositions of the subjectinvention to make them more palatable. Sweetening agents which can beused include aspartame, acesulfame, saccharin salts, dextrose, levulosethaumatin, D-tryptophan, dihydrochalcones, and cyclamate salts.Saccharin salts are preferred. Sweetening agents are generally used inthe subject compositions in amounts of from about 0% to about 6%,preferably from about 0.005% to about 5% by weight.

Oral compositions can also contain a surfactant. Suitable surfactantsare those which are reasonably stable and form suds throughout a wide pHrange, including nonsoap anionic, nonionic, cationic, zwitterionic andamphoteric organic synthetic detergents, and compatible mixturesthereof. Many of these suitable surfactants are disclosed in U.S. Pat.No. 4,051,234, issued to Gieske et al. on Sep. 27, 1977, and in U.S.Pat. No. 3,959,458 issued to Agricola, Briner, Granger and Widder on May25, 1976, both of which are incorporated herein by reference.Surfactants are typically present in compositions of the subjectinvention at a level of from 0% to about 10%, preferably from about 0.2%to about 4% by weight. Surfactants may also be used as solubilizingagents to help retain sparingly soluble components, e.g., some flavoringagents, in solutions. Surfactants suitable for this purpose includepolysorbates and poloxamers.

In preparing oral compositions of the subject invention, it is desirableto add binders and/or thickening agents, particularly to toothpastecompositions. Preferred binders and thickening agents include forexample, carboxyvinyl polymers, polysaccharide gums such as xanthan gum,carrageenan, hydroxyethyl cellulose and water soluble salts of celluloseethers such as sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, andgum tragacanth can also be used. Colloidal magnesium aluminum silicateor finely divided silica can be used as part of the thickening agent tofurther improve texture. These binders and thickening agents aregenerally present in the compositions of the subject invention inamounts of from about 0% to about 6%, preferably from about 0.1% toabout 5% by weight.

Another optional component of the oral carriers of the compositions ofthe subject invention is a humectant. The humectant serves to keeptoothpaste compositions from hardening upon exposure to air, and to givemouthwash and toothpaste compositions a moist feel to the mouth. Certainhumectants can also impart desirable sweetness of flavor to mouthwashand toothpaste compositions. The humectant, on a pure humectant basis,generally comprises from about 0% to about 70%, preferably from about 2%to about 55%, by weight of the compositions herein. Suitable humectantsfor use in compositions of the subject invention include ediblepolyhydric alcohols such as glycerin, sorbitol, xylitol, polyethyleneglycol, and propylene glycol, especially sorbitol and glycerin.

Opacifiers may also be used in toothpastes of the subject invention torender the toothpaste opaque. Suitable opacifiers include titaniumdioxide and some abrasives including, for example, magnesium aluminumsilicate. Opacifiers generally comprise from about 0% to about 4%,preferably from about 0.5% to about 3% by weight of the compositionsherein.

Buffering agents are another optional component of the compositions ofthe subject invention. Suitable buffering agents include anypharmaceutically-acceptable buffers safe for use within the oral cavitywith low affinity for aluminum, gallium or indium. Examples of suchagents include amino acids such as histidine and glycine, as well asions of monocarboxylic acids such as acetate and benzoate. The bufferingagents serve to retain the pH of the compositions within the preferredrange. The amount of buffering agent desirable depends on bufferingcapacity of the particular agent. Generally the buffering agentcomprises from about 0% to about 10%, preferably from about 0.2% toabout 5%, by weight of the compositions herein.

Other optional components of the compositions of the subject inventionare preservatives. The preservatives prevent microbial growth in thecompositions. Suitable preservatives include methylparaben,propylparaben, benzoates and ethanol. If the preservative is ethanol, itgenerally comprises from 0% to about 35% by weight, preferably fromabout 5% to about 15%, of the compositions herein. Other preservativesgenerally comprise from about 0% to about 5% by weight, preferably fromabout 0.1% to about 2%, of the compositions herein.

Antimicrobial, antiplaque agents can also optionally be present in theoral compositions of the subject invention, on the condition that theyare compatible with the Active. Such agents may include, but are notlimited to, triclosan, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, asdescribed The Merck Index, 11th Ed. (1989), p. 1520 (entry No. 9573); inU.S. Pat. No. 3,506,720; and in Eur. Pat. Appl. No. 0,251,591 of BeechamGroup, PLC, published Jan. 7, 1988, chlorohexidine, (Merck Index, No.2090), alexidine (Merck Index, No. 222); hexetidine (Merck Index, No.4624); sanguinarine (Merck Index, No. 8320); benzalkonium chloride(Merck Index, No. 1066); salicylanilide (Merck Index, No. 8299);domiphen bromide (Merck Index, No. 3411); cetylpyridinium chloride,(CPC) (Merck Index, No. 2024); tetradecylpyridinium chloride, (TPC);N-tetradecyl-4-ethypyridinium chloride (TDEPC); octenidine; delmopinol,octapinol, and other piperidino derivatives; nicin preparations;zinc/stannous ion agents; antibiotics such as augmentin, amoxicillin,tetracycline, doxycycline, minocycline, and metronidazole; andperoxides, such as cylium peroxide, hydrogen peroxide, and magnesiummonoperthalate and its analogs as described in U.S. Pat. No. 4,670,252;and analogs and salts of the above antimicrobial antiplaque agents. Ifpresent, the antimicrobial antiplaque agents may comprise from about 0%to about 6%, preferably from about 0.1% to about 5% by weight of thecompositions of the subject invention.

Nutrients can also be present in the oral composition of the subjectinvention, on condition that they are compatible with the Active. Suchagents may include folate, retinoids (Vitamin A), Vitamin C, Vitamin Eand zinc. If present, the nutrients generally comprise from about 0.001%to about 10% by weight of the compositions of the subject invention.

Compositions of the subject invention may also include one or moreanticalculus agents, on the condition that they are compatible with theActive. Anticalculus agents which may be useful in the compositions ofthe subject invention include zinc. Preferred compounds to deliver thezinc are sodium zinc citrate and zinc chloride. The anticalculus agentsgenerally comprise from about 0% to about 15%, preferably from about0.2% to about 13%, more preferably from about 0.4% to about 6% of thecompositions of the subject invention.

Preferred compositions of the subject invention are in the form ofdentifrices. Components of toothpastes generally include a dentalabrasive (from about 10% to about 50%), a surfactant (from about 0.5% toabout 10%), a thickening agent (from about 0.1% to about 5%), ahumectant (from about 10% to about 55%), a flavoring agent (from about0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), acoloring agent (from about 0.01% to about 0.5%) and water (from about 2%to about 45%).

Other preferred compositions of the subject invention are mouthwashesand mouth sprays. Components of such mouthwashes and mouth spraysinclude water (from about 45% to about 95%), ethanol (from about 0% toabout 25%), humectant (from about 0% to about 50%), surfactant agent(from about 0.01% to about 7%), flavoring agent (from about 0.04% toabout 2%), sweetening agent (from about 0.1% to about 3%), and coloringagent (from about 0.001% to about 0.5%). Such mouthwashes and mouthsprays may also include one or more of an anticalculus agent (from about0.1% to about 3%), and an antiplaque agent (from about 0.1% to about5%).

Other preferred compositions of the subject invention are dentalsolutions. Components of such dental solutions generally include water(from about 90% to about 99%), preservative (from about 0.01% to about0.5%), thickening agent (from about 0% to about 5%), flavoring agent(from about 0.04% to about 2%), sweetening agent (from about 0.1% toabout 3%), and surfactant (from about 0% to about 5%).

Oral gel compositions typically include one or more of water (from about0% to about 99%), a humectant such as glycerin (from 0% to about 99%), athickening agent (from about 0.1% to about 5%), a flavoring agent (fromabout 0.04% to about 2%), and a sweetening agent (from about 0.01% toabout 0.5%).

Chewing gum compositions typically include one or more of a gum base(from about 50% to about 99%), a flavoring agent (from about 0.04% toabout 2%) and a sweetening agent (from about 0.01% to about 20%).

Lozenge compositions typically include a lozenge carrier comprising oneor more of a candy base (from about 50% to about 99%), a flavoring agent(from about 0.001% to about 2%, and a coloring agent (from about 0.001%to about 0.5%). Examples of suitable lozenge carriers are disclosed inU.S. Pat. No. 4,931,473 issued Jun. 5, 1990 to Kelleher et al., and inU.S. Pat. No. 4,927,634 issued May 22, 1990 to Sorrentino et al., bothincorporated herein by reference.

The pH of the subject compositions and/or its pH in the mouth can be anypH which is safe for the mouth's hard and soft tissues. Such pH's aregenerally from about 3 to about 7, more preferably from about 4 to about7, more preferably still from about 4.5 to about 6.5.

Methods of Use

Another aspect of the subject invention involves methods for reducing orpreventing dental plaque or gingivitis, by application of compositionscomprising a safe and effective amount of Active, to tissues of the oralcavity. Such compositions are described hereinabove.

These methods involve administering a safe and effective amount ofActive typically by administering an oral composition of the subjectinvention, as described hereinabove to the oral cavity. Generally anamount of at least about 0.05 g of the Active compound is effective. Theteeth and other oral cavity tissues are "bathed" in the Active.

When the oral composition is a toothpaste, typically from about 0.3grams to about 15 grams, preferably from about 0.5 grams to about 5grams, more preferably from about 1 to about 2 grams, of toothpaste isapplied to an applicating device e.g., a toothbrush. The applicatingdevice is then contacted with the oral cavity surfaces in a manner suchthat the oral composition is contacted with tissue of the oral cavity,especially the teeth and gums. The applicating device may be furtherused to effect an even distribution of the oral composition to the toothsurface, for example by brushing. The application preferably lasts for aperiod of from about 15 seconds to about 10 minutes, more preferablyfrom about 1 minute to about 2 minutes. Following application, thetoothpaste residue is typically removed from the tooth surface by usinga liquid acceptable to the oral cavity, typically water, to rinse theoral cavity.

When the oral composition is a mouthwash, typically from about 1 ml. toabout 20 ml., preferably from about 2 ml. to about 15 ml., mostpreferably from about 10 ml. to about 15 ml., of liquid mouthwashcontaining the antiplaque Active is introduced to the oral cavity. Theliquid mouthwash is then agitated for from about 10 seconds to about 30min., preferably from about 15 seconds to about 3 min., more preferablyfrom about 60 seconds to about 2 minutes, within the oral cavity toobtain an improved distribution of the mouthwash over the tissue of theoral cavity. Following agitation, the mouthwash is typicallyexpectorated from the oral cavity.

Application frequency is preferably from about once daily to about 4times daily, more preferably from about 3 times weekly to about 3 timesdaily, more preferably still from about once to about twice daily. Theperiod of such treatment typically ranges from about one day to alifetime.

ORAL COMPOSITION EXAMPLES

The following non-limiting examples further describe and demonstratepreferred embodiments within the scope of the subject invention. Theexamples are given solely for illustration and are not to be construedas limitations of the subject invention as many variations are possiblewithout departing from the spirit and scope of the subject invention.

The compositions of the subject invention can be made using methodswhich are common in the oral products area.

Example I

The following is an example of a mouth rinse formulation and is madeusing conventional processes.

    ______________________________________                                        Component                 Wt %                                                ______________________________________                                        Sorbitol (70% aq)         18.000                                              NaSaccharin               0.040                                               F&DC Blue #1              0.070                                               Ethanol                   8.500                                               Spearmint Flavor          0.118                                               Tween 80                  0.472                                               Pluronic F127             0.157                                               N-acetyl-L-glutamine aluminum salt                                                                      1.000                                               NaOH (1N)                 4.507                                               Water                     q.s.                                                ______________________________________                                    

Example II

The following is an example of a dentifrice formulation.

    ______________________________________                                        Component                 Wt %                                                ______________________________________                                        Sorbitol (70% aq)         49.500                                              NaSaccharin               0.350                                               Dye Solution              0.400                                               Precipitated Silica (J.M. Huber, Inc.)                                                                  20.000                                              Flavor                    1.300                                               Sodium Alkyl Sulfate (27.9% solution)                                                                   5.000                                               Carbopol 940S (B.F. Goodrich)                                                                           0.200                                               Xanthan Gum (Kelco Inc.)  0.600                                               N-acetyl-L-glutamine aluminum salt                                                                      3.000                                               Sodium Hydroxide          0.066                                               Water                     q.s.                                                ______________________________________                                    

The above composition is made by combining the water and part of thesorbitol in an agitated mixture and heating this mixture to about 25° C.(room temperature). The saccharin, N-acetyl-L-glutamine aluminum salt,and precipitated silica are then added in order and the total mixture ismixed for from 5 to 10 minutes. The flavor, dye, and surfactant are thenadded. In a separate vessel the remaining sorbitol, the Carbopol and thexantham gum are slurried together and added to the main tank. After 10minutes of mixing the NaOH is added to adjust the pH. The complete batchis mixed at 70° C. for one-half hour, then milled and deaerated.

While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications to the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of the subject invention.

What is claimed is:
 1. A method for reducing or preventing dentalplaque, or gingival or periodontal diseases comprising contacting toothsurfaces within the oral cavity in humans or lower animals with acomposition comprising a safe and effective amount of a complex of metalions with N-acetylated amino acids wherein the amino acids are selectedfrom the group consisting of naturally occurring amino acids and whereinthe metal ions are selected from the group consisting of In³⁺, Ga³⁺, andAl³⁺ ; and a pharmaceutically-acceptable topical oral carrier whichcomprises a pharmaceutically-acceptable dental abrasive.
 2. The methodof claim 1 for reducing or preventing dental plaque.
 3. The method ofclaim 2 wherein the amino acid is glutamine or cysteine.
 4. The methodof claim 3 wherein the amino acid is glutamine.
 5. The method of claim 3wherein the amino acid is cysteine.
 6. The method of claim 3 wherein themetal ion is Al³⁺.
 7. The method of claim 6 wherein the compositioncomprises from about 0.05% to about 10% by weight of the complex.
 8. Themethod of claim 7 wherein the composition comprises about 0.1% to about5% of the complex.
 9. The method of claim 7 wherein the pH of thecomposition is from about 3 to about
 7. 10. The method of claim 8wherein the pH of the composition is from about 4 to about
 7. 11. Anoral care composition for reducing or preventing dental plaque, orgingival or periodontal diseases comprising a safe and effective amountof a complex of metal ions with N-acetylated amino acids wherein theamino acids are selected from the group consisting of naturallyoccurring amino acids and wherein the metal ions are selected from thegroup consisting of In³⁺, Ga³⁺, and Al³⁺ ; and apharmaceutically-acceptable topical oral carrier which comprises apharmaceutically-acceptable dental abrasive.
 12. The oral carecomposition of claim 11 wherein the amino acid is glutamine or cysteine.13. The oral care composition of claim 12 wherein the amino acid isglutamine.
 14. The oral care composition of claim 12 wherein the aminoacid is cysteine.
 15. The oral care composition of claim 12 wherein themetal ion is Al³⁺.
 16. The oral care composition of claim 15 wherein thecomposition comprises from about 0.05% to about 10% by weight of thecomplex.
 17. The oral care composition of claim 16 wherein thecomposition comprises about 0.1% to about 5% of the complex.
 18. Theoral care composition of claim 16 wherein the pH of the composition isfrom about 3 to about
 7. 19. The oral care composition of claim 18wherein the pH of the composition is from about 4 to about
 7. 20. Theoral care composition of claim 19 wherein the pH of the composition isfrom about 4.5 to about 6.5.